Our long-term objective is to elucidate the underlying mechanisms of neuronal death in Parkinson's disease (PD). The identification of several genes exhibiting linkage to PD has not yet led to the understanding of how their protein products bring about cell death. Though in vitro studies have been instrumental in identifying potential mechanisms of neurodegeneration, their findings need to be corroborated in vivo. I propose to utilize Drosophila genetics to investigate putative protein interactions among three PD-linked genes: synphilin-1, alpha-synuclein, and parkin. My primary strategy will be to investigate the inherent toxicity of synphilin-1 and its PD-associated mutation, R621C. Furthermore, genetic interactions between both forms of synphilin and either alpha-synuclein or parkin will be examined. These efforts will culminate in the investigation of genetic interactions among synphilin-1, alpha-synuclein, and parkin.